p-substituted benzene sulphonamides



United States atent Ofiice 2,858,318 Patented Oct. 28, 1958 2,858,318 p-SUBSTITUTED BENZENE SULPHONAMIDES No Drawing. Application April 8, 1957 Serial No. 651,143

Claims priority, application Switzerland April 19, 1956 6 Claims. (Cl. 260-302) The present invention concerns processes for the production of new p-substituted benzene sulphonamides as well as the compounds obtained according to these processes which have valuable pharmacological properties.

After sulphanilamide had been used widely in chemotherapeutics, Mann and Keilin, Nature 146, 164 (1940) found that it inhibited carbonic anhydrase whilst the numerous N -substituted chemotherapeutic active substances had no such action.

Surprisingly it has now been found that p-substituted benzene sulphonamides which correspond to the general formula:

in which R represents hydrogen or an alkyl, alkoxyalkyl, carboxy, carbalkoxy, carbamyl, cycloalkyl, aralkyl, aryl, hydroaryl, furyl, thienyl or thienylalkyl radical and wherein any aromati ring in R can be substituted by halogen, alkyl, alkoxy, alkylendioXy, amino, acylamino, carboxy, carbalkoxy, carbamyl, sulphamyl or sulphonic acid groups, R by itself represents hydrogen, an alkyl, alkenyl, aralkyl or dialkylaminoalkyl radical, an alkyleniminoalkyl radical having 56 ring members or a morpholino alkyl radical, X by itself represents oxygen, NH or NR or X-R together represents an alkylenirnino radical having 56 ring members or the morpholino radical, and n represents 0 or 1, inhibit carbonic anhydrase considerably more than simple aromatic sulphonamides such as sulphanilamide or p-sulphamyl benzoic acid.

Such compounds can be produced in a simple manner by condensing p-thiocarbamyl benzene sulphonamide (psulphamylthiobenzamide), of the general Formula II with compounds, in particular halogen oXocarboXylic acid esters, of the general Formula III, according to the rewherein R and R have the meanings given for the radicals R and -COX-R respectively but in addition also represent further radicals which can be converted into carboxy groups by hydrolysis and/or oxidation or, in the case of R can also contain such radicals, Hal represents chlorine or bromine, and n represents 0 or 1.

Compounds which contain one or more carbalkoxy groups or which contain other radicals which can be converted into carboxy groups by hydrolysis or by hydrolysis and subsequent oxidation, may then be partially hydrolysed in such a manner that the sulphonamide group is retained, the partial hydrolysis being performed advantageously in an alkaline medium, and then or instead of the partial hydrolysis, oxidising any oxidisable groups liberated by the partial hydrolysis or originally present to carboxy groups if necessary. If desired, compounds which contain carboxy groups can then be converted into compounds having halogenocarbonyl groups by treating them with inorganic acid halides and the compounds having halogenccarbonyl groups or, if desired, also compounds which contain carbalkoxy groups, can be reacted with compounds of the general formula:

wherein R and X have the meanings given above.

According to a further process, the p-substituted benzene sulphonamides as defined can be produced by reacting p-substituted benzene sulphonic acid derivatives, in particular benzene sulphochlorides of the general formula:

S V in which Y represents chlorine, bromine or an aryloxy group and R, and R have the meanings given for the radicals R and CO-XR respectively but in addition R" can represent a halogenocarbonyl group or a radical R which contains a halogenocarbonyl or a halogenosulphonyl group instead of carbamyl groups or a sulphamyl group, and R; can represent a halogenocarbonyl group, and n has the meaning given above, with the amount of ammonia corresponding to the number of acid halide groups present, the reaction being performed in the presence of an acid binding agent, advantageously in excess ammonia. The sulphohalides necessary as starting materials for this process are new in themselves and can be produced by processes known per so which will be more closely described below.

Finally, p-substituted benzene sulphenamides of the general formula:

S VI

can be converted into p-substituted benzene sulphonamides of the general Formula I by treatment with oxidising agents such as e. g. potassium permanganate.

The condensation according to the first production process can be performed with good yields, e. g. by heating the reaction components in aqueous alcohol without any condensing agents or catalysts. In particular the ethyl and methyl esters of a-acyl-ahalogen acetic acids are used as halogen oxocarboxylic acid derivatives. EX-

amples of such are the Ot-Cl'llOl'O- and a-bromo-acetoacetic acid ethyl esters and methyl esters, propionyl, butyryl, isobutyryl, isovaleryl, enanthyl, caprylyl, dibutylacetyl, methoxyacetyl, bonyl, cyclohexane acetyl, phenyl acetyl, m.p-dimethylphenyl acetyl, ,B-phenyl-propionyl, ,B-(mp-dimethylphenyl)-propionyl, 'y-phenyl-butyryl, ,8-phenyl-isobutyryl, benzoyl, p-methyl-benzoyl, mp-dimethyl-benzoyl, p-anisoyl, p-chloro-benzoyl, piperonylyl, zoyl, hydroindenyl-(5)-acetyl, 1.2.3.4-tetra-hydro-1-naphthoyl, furoyl, thiophene-(2)-carbonyl and fi-thienyl-propionyl bromoacetic acid ethyl esters or chloroacetic acid ethyl esters, bromo-oxalacetic acid diethyl ester and pcarbethoxy-benzoyl bromoacetic acid ethyl ester. End products in Which n represents 1 are obtained e. g. by using ,B-acyl-fi-halogen propionic acid alkyl esters such as the methyl and ethyl esters of ,B-chloroand fl-bromolevulinic acid and Bbenzoyl-5-bromo-propionic acid. If, instead of halogen oxocarboxylic acid derivatives, derivatives of halogen malonic dialdehydes are used for eX- ample such as the a-bromopfl-diethoxy propionaldehyde,

cyclopropancarbonyl, cyclohexane car-i p-acetylamino-benthen on condensing with p-sulphamyl thiobenzamide, 2- (p-sulphamyl-phenyl)-thiazole--aldehyde is obtained, i. e.' a compound having a radical R which can be converted by oxidation into the carboxy group. The oxidation is performed by the methods known for the conversion of an aldehyde into a carboxylic acid such as e. g. oxidation with oxygen or air in the presence of heavy metal catalysts. The oxidation can also be performed with hydrogen peroxide, potassium permanganate in alkaline solution, diluted nitric acid, chlorine or bromine water.

p-Substituted benzene sulphochlorides of the general Formula V can be reacted direct or after solution in inert solvents with excess ammonia, if necessary on heating. The starting materials necessary for this process can be obtained e. g. by oxidising chlorination of p-[S-carboxythiazolyl-(2)]-phenyl benzyl sulphides, which may be substituted in the 4-position, or of bis-[p-5-carboxy-thiazolyl- (2)-phenyl]-disulphides as well as of the esters thereof. p-Substituted benzene sulphochlorides of the general Formula V can also be produced by reducing a p-[S-carboxy-thiazolyl-(2)]-nitrobenzene which may be substitued in the 4-position, to the amino compound, converting this into the corresponding diazonium chloride and treating the latter with sulphur dioxide in a non-water containing solution. On reacting sulphur dioxide in a solution containing water; first a sulphinic acid is obtained which can be converted by methods known per se into the corresponding sulphochloride. The benzene derivatives used in the above process which have a substituted thiazolyl radical in the p-position to a radical which is capable of being converted, such as the benzyl sulphides, disulphides or 4-substituted p-[S-carboxy-thiazolyl-(Z)lnitrobenzenes and the esters thereof are obtained in a manner analogous to the first production process named by using p-benzylmercapto-thiobcnzamide, p.p'-dithio-bis-thiobenzamide or p-nitrothiobenzamide for the condensation with halogen oxocarboxylic acid esters of the general Formula III instead of p-sulphamyl thiobenzamide, and, possibly hydrolysing the p-[5-carbalkoxy-thiazolyl-(2}l-bcnzene derivatives obtained.

The p-substituted benzene sulphenamides of the general Formula VI which are starting materials for the third general production process are obtained for example from the p-[5-carboxy-thiazolyl-(2)l-phenyl benzyl sulphides mentioned in the previous paragraph, from bis-p-[S-carboxy-thiazolyl-(2)-phenyl]-disulphides, from Z-(p-mercapto-phenyD-thiazole-S-carboxylic acids obtained therefrom by reduction as Well as from the esters corresponding to all these acids, by reacting with alkali hypochlorites in the presence of ammonia.

The following examples further illustrate the production of the new compounds. Parts are given as parts by weight. Their relationship to parts by volume is as that of grammes to cubic centimetres. The temperatures are in degrees centigrade.

EXAMPLE 1 21.6 parts of p-sulphamyl thiobenzamide are dissolved in 200 parts by volume of 50% alcohol and 15.0 parts of u-chloracetoacetic acid methyl ester are added at 50. After boiling for 15 hours, the reaction mixture is cooled and filtered. The 2-(p-sulphamyl-phenyl)-4-methyl thiazole-S-carboxylic acid methyl ester obtained (MP. 216) is saponified by boiling with diluted caustic soda lye. On acidification of the solution, 2-(p-sulphamyl--phenyl)- 4-methy1 thiazole-S-carboxylic acid is obtained in the form of fine crystal needles. (M. 1?. 248 from methanol, with decomposition.)

EXAMPLE 2 45.5 parts of formyl chloroacetic acid ethyl ester are refluxed for 3 hours with 150 parts by volume of alcohol, 50 parts of water and 79 parts of p-sulphamyl thiobenzamide. After cooling, the crystals are drawn off under suction and recrystallised from alcohol. 2-(p- 4 sulphamyl-phenyD-thiazole-5-carboxylic acid ethyl ester melts at 213-215". A further amount is obtained by concentrating the mother liquors.

To saponify the ester, 6 parts thereof are heated to for 2 hours in parts of 2 N-caustic soda lye. The Z-(p-sulphamyl-phenyD-thiazole-S-carboxylic acid is precipitated by the addition of concentrated hydrochloric acid until the reaction is clearly acid to Congo red paper. It is drawn off under suction, dried and recrystallised from alcohol; it decomposes at about 246.

EXAMPLE 3 31 parts of benzoyl chloroacetic acid ethyl ester, 300 parts by volume of alcohol and 29 parts of p-sulphamyl thiobenzamide are refluxed for 15 hours. The reaction mixture is then cooled and the precipitated crystals of 2-(p-sulphamyl-phenyl)-4-phenyl thiazole 5 carboxylic acid ethyl ester are drawn off under suction.

After recrystallising from alcohol, the ester melts at 2095-211".

3.2 parts of this ester are heated for 3 hours in a water bath with 20 parts by volume of 2 N-caustic soda lye, the solution is acidified while warm with concentrated hydrochloric acid and the 2-(p-sulphamyl-phenyl)-thiazole-4- phenyl-S-carboxylic acid is filtered off under suction. It precipitates in a fairly pure form and decomposes at 251-252".

EXAMFLE 4 8 parts of phenylacetyl-chloroacetic acid ethyl ester. are refluxed for 6 hours with 30 parts by volume of alcohol, 20 parts of Water and 7 parts of p-sulphamyl thiobenzamide. The reaction product is worked up as described in Example 1. The melting point of the pure 2-(psulphamyl-phenyl)-4-benzyl thiazole ,5 carboxylic acid ethyl ester is 209-2l1. It is saponifiedas-described in Example 1. 2-(p-sulphamyl-phenyl)-4-benzyl thiazole-5- carboxylic acid decomposes at about 23-8-239.

EXAMPLE 5 EXAMPLE 6 33 parts of chloro-oxalacetic acid diethyl ester are refluxed for 6 hours with 33 parts of p-sulphamyl thiobenzoamide and 200 parts by volume of alcohol. The product is worked up as described in Example 1. The pure 2-(psulphamyl-phenyl)-thiazole-4.S-dicarboxylic acid diethyl ester melts at l37-139.

Saponification is performed as described in Example 1. The Z-(p-SuIphamyl-phenyl)-thiazole-4.S-dicarboxylic acid decomposes at about 237.

EXAMPLE 7 33 parts of [3-bromo-levulinic acid ethyl esterare re-. fiuxed for 4 hours with parts by volume of alcohol and 32 parts of p-sulphamyl thiobenzamide. The product is worked up as described in Example 1. The pure 2-(psulphamyl-phenyl)-4-methyl-thiazole-5-acetic acid ethyl ester melts at 149-151".

Saponification is performed as described in Example 1. The 2-(p-sulphamyl-phenyl)-4-methyl thiazole-S-acetic acid decomposes at about 203-205 In the following table, the esters A and the correerein R and have the meanings given and It always represents 0, can be obtaine in the above examples:

(1 by the processes described Table I A B x No. Rx -o-x-R=o000,m GO-X-R:-=-OO0H M. P., degrees Decomposition, degrees 5 CH-CHr- 180-181. 5 245. 5-243 3 CEO 170-179 234-235 9 OIO 2305-22 240-242 CH] 10 CHI-0114- 177.5-190 237-2395 11 OHPOHI 102-105 232-233 Cg: 12 I /CH 195-197 212-273 14 OHa-O-OHP 143-145 236-238 S 1o (methyl ester 239-240) 252-254 17 (11--O4H3)2CH 176-178 L71 in H 18 (CHQQCH- CH; 159-171 222-224 19 i H i- 1s1-1s3 239-240 21 cm-O-om-orw 137-194 T dble l ."--'Continued No. R1 -GD -X-Rz=COOCzH5 -COX-Rn=COOH M. P., degrees Decomposition, degrees 23 I1-C7H15 135-137 24.. Il-oaH1r 153-155 25: =CHi-'-OH=OH' 163 164 2e Gem-H- 111-173 S CHr-OHr- EXAMPLE 8.

29.8 parts of Z-(p-sulphamyl-phenyl)-4-methyl-thiazole- 5-carboxylic acid are refluxed for 8 hours with 175 parts of thionyl chloride and the excess thionyl chloride is distilled ofl? inz-the vacuum. To obtainthe most complete removal of thionyl chloride possible, petroleum ether or another inert solvent is'added twice. The wax-like residue is rubbed with 50 parts by volume of a aqueous ammonia solution until it becomes pulverulent; It is then filtered off, washed with water and recrystallised from alcohol. 2-(p-sulphamyl-phenyl)-4-methyl thiazole-5-carboxylic acid amide melts at 266.

2-(p-sulphamyl-phenyl) -4-methyl-thiazole-5-earboxylic acid diethyl-amide (M. P. 181193.-) and Z-(p-sulphamylphenyl)-4-methyl-thiazole-5-carboxylic acid diethylamino ethylamide (M. P. 162164) are obtained in an analogous manner from the above mentioned carboxylic acid chloride and the corresponding amines.

EXAMPLE 9 The wax-like crude carboxylic acid chloride mentioned in Example 8 is heated for 1 hour in a water bath with 100 parts of lmorpholine. The solution obtained is poured EXAMPLE 11 The residue described in Example 10 is dissolved in hot chloroform and poured into parts of morpholine. The mixture is then evaporated to dryness in the vacuum and the. residue is. recrystallised from diluted alcohol. The 2- (p-sulphamyl-phenyl) -4-isobutyl-thiazole-S-carboxylicacid morpholide so obtained melts at 211-213 EXAMPLE 12 3420 parts of 2+(p-sulphamyl-phenyl) 4 isobutyl-thiazole-S-carboxyliczacid are converted into the acid chloride according to Example-10. The crude product is refiuxed' for 1 hour: with 200 parts of benzyl alcohol and 130 parts of. pyridine. After evaporating off the excess benzyl alcohol and the pyridine in the vacuum, a crystalline residue consisting of Z-(p-sulphamyl-phenyl)-4-isobutyl-thiazole-S-carboxylic acid benzyl ester is obtained. After recrystallising from'alcohol, it melts at 172-174.

In an analogous manner, the esters given in Table II are obtained from the above acid chloride or the 2-(psnlphamyl phenyl) 4 methyl thiazole 5 carboxylic acid chloride produced according to Example 8 and from the 'corresp onding alcohols into water whereupon 2(p-sulphamyl-phenyl)-4-methylthiazole-S-carboxylic acid morph'olide separates out. After recrystallising from alcohol it melts at 223226.

EXAMPLE 10 34.0 parts of 2-(p-sulphamyl-phenyl)-4-isobutyl-thiazole-S-carboxylic acid are refluxed for half an hour with 175 parts of thionyl chloride and 0.5 part of pyridine and then evaporated to dryness in the vacuum. The waxlike residue is rubbed with 200 parts of a 25% aqueous ammonia until it becomes pulverulent when it is filtered off. The 2-(p-sulphamyl-phenyl)-4-isobutyl-thiazole-5- carboxylic acid amide so obtained is recrystallised from N-bl'lt'alnol and melts at 199-201 Daily doses of -500 mg. of the compounds according to the present invention, e. g. of 2-(p-sulphamylphenyl)-4-is0propyl thiazole 5 carboxylic acid ethyl ester or of 2-(p-sulphamylrphenyl) 4 benzyl-thiazole-S- carboxylicacid are administered perorally to obtain a good diuretic effect in man. The daily dosage necessary can be containedin, for example, l-2 tablets or other dosage unit forms;

What we claim is:

1. A p-substituted benzene sulphonamide corresponding to the formula:

wherein R represents a member selected from the group consisting of hydrogen, lower alkyl, methoxymethyl, -COOH, cyclohexyl, fl-phenylethyl, benzyl, 'y-phenylpropyl, dimethylbenzyl, phenyl, chlorophenyl, methylphenyl, methoxyphenyl, methylendioxyphenyl, carboxyphenyl and carbethoxyphenyl; R by itself represents a member selected from the group consisting of hydrogen, lower alkyl, benzyl and diethylaminoethyl; X by itself represents a member selected from the group consisting of oxygen and NH; XR together represent the diethylamino group and the morpholino group; and n represents one of the numerals 0 and 1.

2. 2 (p sulphamyl phenyl) 4 isopropyl thiazole- 5 carboxylic acid ethyl ester.

3. 2 (p sulphamyl phenyl) 4 benzyl thiazole- 5 carboxylic acid.

4. 2 (p sulphamyl phenyl) 4 isobutyl thiazole- 5 carboxylic acid amide.

5. 2 (p sulpharnyl phenyl) 4 (p chlorophenyl)- thiazole 5 carboxylic acid.

6. 2 (p sulphamy1- phenyl) 4 cycIohexyl-thiazole- 5 carboxylic acid methyl ester.

No references cited. 

1.A P-SUBSTITUTED BENZENE SULPONAIDE CORRESPONDING TO THE FORMULA: 